Olanzapine‐induced cardiomyopathy: A mimicker of obesity cardiomyopathy?

Abstract Olanzapine, an atypical antipsychotic medication, has gained prominence in the treatment of schizophrenia and related psychotic disorders due to its effectiveness and perceived safety profile. However, emerging evidence suggests a potential link between olanzapine use and adverse cardiovascular effects, including cardiomyopathy. This narrative review explores the mechanisms, clinical implications, and management strategies associated with olanzapine‐induced cardiomyopathy. A comprehensive review of the literature was conducted to investigate the relationship between olanzapine and cardiomyopathy. The search included epidemiological studies, clinical case reports, and mechanistic research focusing on the pathophysiology of olanzapine‐induced cardiomyopathy. The review also examined treatment strategies for managing this potential complication. Olanzapine‐induced cardiomyopathy is hypothesized to be associated with metabolic disturbances and receptor antagonism. The metabolic effects of olanzapine, such as weight gain, insulin resistance, and dyslipidemia, share similarities with obesity‐related cardiomyopathy. Additionally, olanzapine's antagonism of certain receptors may contribute to cardiovascular stress. The review highlighted that patients with new‐onset heart failure and significant weight gain while on olanzapine should be closely monitored for signs of cardiomyopathy. Early detection and prompt withdrawal of olanzapine, along with initiation of goal‐directed medical therapy, are crucial for mitigating this potentially life‐threatening condition. The relationship between olanzapine and cardiomyopathy is complex and not yet fully understood. However, the potential for significant cardiovascular risk necessitates vigilance among healthcare providers. Early identification and management of olanzapine‐induced cardiomyopathy can improve patient outcomes. Further research is needed to elucidate the precise mechanisms behind this adverse effect and to develop optimized treatment strategies for patients requiring antipsychotic therapy.

The advent of antipsychotic medications in the 1950s represented a significant turning point in the treatment of schizophrenia and other psychotic disorders, thereby introducing a new era of therapeutic possibilities. 1 Despite notable advancements in managing these conditions, the efficacy of antipsychotics is often limited by their adverse effects. 1 Cardiomyopathy is a rare but reported complication of antipsychotic medications, with a few cases documented in the literature. 2,3Although clozapine-induced cardiomyopathy has been more frequently reported, there is a risk of myocarditis associated with first-generation antipsychotics such as haloperidol and fluphenazine. 2,4Olanzapine, an atypical antipsychotic belonging to the thienobenzodiazepine class, has gained widespread use owing to its perceived safety compared to its predecessor, clozapine. 1,2In recent years, olanzapine has seen an increase in its use for treating negative psychiatric symptoms due to its more favorable side effects profile compared to first-generation antipsychotics, with a lower risk of extrapyramidal side effects.However, olanzapine has the potential to cause life-threatening hematological side effects such as agranulocytosis. 2,5It is commonly prescribed for the treatment of multidrug-resistant schizophrenia, acute severe agitation, and behavioral bipolar disorder.
There is growing concern regarding the potential association between olanzapine use and adverse cardiovascular outcomes, particularly cardiomyopathy and conduction abnormalities. 2,4,68][9] Furthermore, olanzapine has been associated with severe heart and muscle conditions, including myocarditis and rhabdomyolysis. 3Although olanzapine is commonly considered safe about corrected QT interval, it still poses risks related to weight gain and cardiovascular health. 10There have been reported cases of olanzapine-inducing myocarditis and rhabdomyolysis, even after a considerable time following the initiation of treatment. 3ailable evidence suggests that the incidence of olanzapineinduced cardiomyopathy is relatively low.However, individual patient factors, such as pre-existing cardiovascular conditions, may contribute to its development. 1,11Despite the unclear mechanism, metabolic disturbances resulting from weight gain have been proposed as a potential pathway for olanzapine-induced cardiomyopathy, as weight gain is an independent risk factor for cardiovascular complications. 12 a study of 80 patients taking olanzapine, 60 completed the study, and 66.6% experienced a weight gain of 1−5 kg over 4 weeks. 1 Notably, the incidence of olanzapine-induced weight gain was higher in females (60%) than males (40%).
Interestingly, the dose of the drug was not correlated with the incidence of weight gain.4][15] The prevalence of olanzapineinduced cardiomyopathy is challenging to determine due to the scarcity of large-scale, prospective studies. 10,11This article provides a comprehensive review of olanzapine-induced cardiomyopathy, highlighting its potential resemblance to obesityrelated cardiomyopathy.

| Symptoms of olanzapine-induced cardiomyopathy
The administration of olanzapine may result in the emergence of cardiomyopathy, a condition that can present with several symptoms, including chest discomfort, shortness of breath, generalized edema, and signs of heart failure (HF), such as reduced ejection fraction and enlarged heart chambers. 16Patients who are prescribed olanzapine may commonly experience adverse effects such as weight gain, diabetes, elevated lipid levels, and a lengthened QT interval. 16though the development of cardiomyopathy due to olanzapine is rare, it is crucial to consider this possibility in patients experiencing cardiac symptoms while on medication.Prompt recognition, cessation of the drug, and effective management of HF are critical for preventing long-term damage to the heart muscle in such cases. 16ntinuous monitoring of patients taking olanzapine for potential cardiovascular complications is paramount to ensuring prompt intervention and care.

| Olanzapine use, weight gain, and cardiovascular hemodynamics
Research has established a dose-dependent relationship between HF and body mass index (BMI), with a 2016 meta-analysis revealing a 41% increase in HF risk for every 5 kg/m 2 increase in BMI. 17 This association involves several factors, including heightened cardiac stress, altered hemodynamics, sympathetic drive, and elevated risks of concurrent cardiovascular conditions such as diabetes, hypertension, hyperlipidemia, and sleep apnea.
The pathophysiology of cardiomyopathy in patients receiving olanzapine therapy is rooted in the heart's challenge to meet metabolic demands despite a higher-than-normal cardiac output (CO), termed "metabolic cardiomyopathy." 18In obese individuals, CO can reach levels as high as 10 L/min, compared to 5−6 L/min in those with average weight. 19Long-term implications of metabolic cardiomyopathy include cardiac remodeling marked by left ventricular (LV) hypertrophy, cardiac fibrosis, and diastolic dysfunction, ultimately leading to HF.The abnormal accumulation of fat, as observed in olanzapine use, drives increased CO and workload, resulting in disproportionate LV hypertrophy to meet energy and metabolic demands, particularly evident in patients with chronic olanzapine use. 20This aberrant fat deposit also impacts the heart's contractility, relaxation, and survival, potentially leading to HF. 21,22 Similar to obesity-induced cardiomyopathy, olanzapine-induced cardiomyopathy can manifest as systolic, diastolic, or combined HF. 23,24 Additionally, individuals using olanzapine are more likely to be obese, predisposing them to comorbidities such as hypertension, sleep apnea, or diabetes mellitus.These conditions, in turn, increase the risk of anatomic and morphological myocardial pathologies, including myocardial infarction, arrhythmias, and HF. 25 Figure 1 outlines the proposed steps in the mechanism of weight gain associated with olanzapine use, including its effect on appetite, neurotransmitter signaling, and metabolic processes, ultimately resulting in increased calorie intake and decreased energy expenditure, leading to weight gain.
2.3 | Hemodynamic alterations driving HF in chronic olanzapine use include

| Elevated blood pressure
Olanzapine has been linked to obesity, a primary risk factor for hypertension, 26,27 although the underlying mechanism remains incompletely understood.Possible mechanisms include sodium retention, increased sympathetic stimulation, and activation of the RAAS pathway. 28,29Metabolic syndrome, comprising hypertension, dyslipidemia, and hyperglycemia, is implicated in 45−50% of cardiovascular diseases (CVDs), including HF and myocardial infarction. 30

| Arterial stiffness
Chronic olanzapine use results in excessive fat deposition in blood vessels, leading to decreased distensibility and increased vascular stiffness.This contributes to endothelial dysfunction, extracellular matrix remodeling, calcification, and inflammation, culminating in elevated blood pressure and increased myocardial wall stress.[33][34][35][36]

| Peripheral vascular resistance (PVR), increased CO, and blood volume
Hypertension's association with elevated peripheral vascular resistance inversely correlates with BMI, leading to increased CO. 37 Additionally, increased blood volume exacerbates sodium retention and metabolic demands, triggering the sympathetic nervous system and RAAS activation while downregulating natriuretic peptides.These alterations impair sodium excretion and contribute to hypertension, predisposing to volume overload and high-output HF. 17,[38][39][40][41][42][43]

| Increased LV wall stress
Elevated blood volume, stroke volume, and CO contribute to LV wall stress, resulting in LV dilatation and eccentric hypertrophy, which leads to diastolic dysfunction.Systolic dysfunction may ensue when LV dilatation fails to compensate for excessive wall stress and thickening. 44

| Pulmonary hypertension
The precise mechanism underlying pulmonary hypertension in chronic olanzapine use remains unclear.It may involve an interplay between increased LV filling pressure and pulmonary capillary wedge pressure typically associated with LV failure. 45Furthermore, the increased risk of sleep apnea and obesity hypoventilation syndrome in patients on chronic olanzapine therapy may contribute to hypoxic vasoconstriction.[48]

| Proposed mechanism of olanzapine-induced cardiomyopathy
As previously discussed, olanzapine-induced myopathy arises from obesity/metabolic cardiomyopathy, attributed to olanzapine's potential to induce obesity and metabolic dysregulation.This process involves a complex interplay among adipose tissue dysfunction and inflammation, metabolic disturbances, calcium handling, and autophagy.
Olanzapine initiates obesity, triggering a progressive pathological cascade characterized by activating adipocytes and resident immune cells, leading to the release of proinflammatory cytokines. 49In obesity, elevated levels of proinflammatory cytokines such as adiponectin, leptin, resistin, nitric oxide, interleukins, tumor necrosis factor (TNF), and other inflammatory mediators interact with systemic changes, including increased insulin resistance, RAAS activation, lipotoxicity, and interstitial fibrosis, contributing to CVD development in olanzapine-treated patients.
The primary trigger is the excess adiposity resulting from olanzapineinduced metabolic dysregulation.Adipose tissue dysregulation and inflammation directly and indirectly exacerbate cardiomyopathy.Moreover, excessive adipose tissue deposition promotes insulin resistance, impaired glucose and lipid metabolism, and systemic inflammatory reactions, including the release of interleukins (IL-6, 10, 13, 14), TNF, and diffuse macrophage activation.[52] Animal studies have corroborated these findings, further supporting the role of olanzapine exposure in cardiomyopathy development. 53Figure 2 below provides a visual summary of the proposed mechanism of olanzapine-induced cardiomyopathy.

| Timeline of olanzapine-induced cardiomyopathy
The development of cardiomyopathy due to olanzapine can vary among individuals, as reported in the literature.For instance, a 28-year-old patient developed dilated cardiomyopathy after nearly a decade of olanzapine treatment, 16 and another study found a connection between clozapine and HF within 3 years but did not establish an association between olanzapine, quetiapine, and the cardiac adverse events under investigation. 54Although the timeline for the onset of olanzapine-induced cardiomyopathy has not yet been standardized, it is essential to monitor patients regularly for signs of cardiac dysfunction, particularly those receiving long-term olanzapine therapy.Prompt identification and discontinuation of the medication are critical to prevent irreversible myocardial damage in such cases. 16,55

| Treatment of olanzapine-induced cardiomyopathy
Managing olanzapine-induced cardiomyopathy requires prompt recognition of the condition, cessation of medication, and effective management of symptoms of HF.Discontinuing the drug is crucial to alleviate further harm to the myocardium. 16,55Patients diagnosed with this condition may necessitate standard HF treatment strategies, such as fluid restriction, digoxin, ACE inhibitors, β-blockers, and diuretics. 16I G U R E 2 Mechanisms involved in olanzapine-induced cardiomyopathy.
These therapeutic agents aim to improve cardiac function and alleviate symptoms associated with HF.Regular monitoring and subsequent evaluations are vital for assessing the patient's response to treatment and adapting the management regimen as needed. 16rthermore, studies suggest that consistent physical activity can help counteract the adverse effects caused by olanzapine, including metabolic issues like weight gain and insulin resistance, which elevate the risk of cardiovascular complications. 56In addition to exercise, dietary adjustments to maintain a healthy weight and regulate metabolic indicators such as blood sugar levels and lipid profiles can prove advantageous in managing olanzapine-induced cardiomyopathy. 56Embracing lifestyle modifications centered on a wellrounded diet, weight control, and regular physical activity can complement medical interventions and enhance the prognosis for individuals grappling with this condition. 16

| CONCLUSION
In summary, olanzapine is a significant advancement in the treatment of schizophrenia and related psychiatric disorders.However, it is essential to closely monitor patients taking medication because of its potential association with cardiomyopathy, particularly in obese patients.The detection of olanzapine-induced cardiomyopathy requires a high level of suspicion, as new-onset HF in patients receiving olanzapine without a prior cardiac history, especially when accompanied by weight gain, should raise concerns.Recent case reports have illustrated this point. 54The proposed mechanisms for olanzapine-induced cardiomyopathy include metabolic disturbances and adipose tissue dysfunction, highlighting the complexities involved.Early discontinuation of olanzapine upon suspicion has resulted in symptom improvement, and the management of HF with goal-directed medical therapy (GDMT) is crucial for the prognosis of olanzapine-induced cardiomyopathy.Further research is necessary to determine the optimal exposure duration, treatment strategies, and prognosis.In addition, it is essential to elucidate the precise pathophysiology and develop optimal management strategies for olanzapineinduced cardiomyopathy.